Project summary: Antibodies are the crown jewel of humoral adaptive immune responses and, plasma cells (PCs) are by far the most specialized and main antibody-secreting cells. PCs differentiate from B lymphocytes following microbial- or CD4 T cell-induced differentiation. Depending on the B cells from which they derive, PCs will largely secrete IgM, IgG or IgA. Until very recently, PCs were viewed exclusively as antibody-producing factories. Here we show for the first time that a large subset of splenic PCs bearing surface IgM (IgM+ PCs) have a strikingly high phagocytic capacity. In contrast, all class-switched PCs (i.e., IgG+ PCs) lack this capacity. Thus, our discovery that plasma cells, a central component of adaptive immunity, play a critical innate immune role, is potentially transformative. The overarching goal of this proposal is therefore to explore the consequences of this previously unrecognized phagocytic capacity of IgM+ PCs both in innate and adaptive immunity. Phagocytosis has evolved from playing a key function in innate immunity and tissue remodeling to having a pivotal role at the crossroads between innate and adaptive immunity. This ancient function is traditionally thought to be performed by professional phagocytes, including polymorphonuclear cells (PMNs), monocytes and macrophages and peritoneal cavity B-1 B cells. Our preliminary data, indicates the existence of a new phagocyte type, phagocytic plasma cells (PhPCs), which have the potential to play novel roles in immunity. Thus far, our preliminary studies have shown that PhPCs in vitro and in vivo phagocytose a variety of targets, including latex beads and E. coli. Critically, upon lipopolysaccharide (LPS) treatment of mice, we observe a ~16 fold increase in splenic PhPCs numbers, which represents ~1% of total splenocytes. Moreover, PhPCs express surface CD86 and MHC II and, 3D confocal imaging have revealed that many PCs are in close proximity to CD4 T cells, thus suggesting a biological significance in their potential capacity to present antigen. Our new findings have lead us to hypothesize previously unrecognized antibody-independent roles of splenic PhPCs in innate and adaptive immunity, including: 1- Their control and clearing of microbes; 2- Their modulation of immunity through cytokine and chemokine secretion; 3- Their capacity to present phagocytosed antigens to T cells and thus, initiate adaptive immune responses. To test these hypotheses, we will be using mice conditionally lacking Blimp-1 in the B-cell compartment (Blimp-1-cKO mice). Critically, these Blimp-1-cKO mice lack PCs, thus making it possible to compare potential differences between mice with and without splenic PCs. The specific aims of this proposal are: AIM 1. To investigate key roles of PhPCs in phagocytosis-elicited innate immune mechanisms; AIM 2. To characterize the mechanisms by which PhPCs bridge innate with adaptive immunity. Our discovery of PhPCs represents a paradigm shift in our understanding of plasma cell biology and their roles in immunity. Thus, our proposed studies will further our basic understanding of these cells in health and diseases. Moreover our studies will provide with the knowledge for using these cells as immunotherapeutic tools.